1. Field of the Invention
This invention relates to 2-carbamoyloxymethylpenicillins, 3-carbamoyloxycephalosporins and desacetoxy cephalosporins, and to their preparation by reaction of a penicillin sulfoxide with an isocyanate.
2. Description of the Prior Art
(A) U.S. Pat. No. 3,275,626 discloses, inter alia, the preparation of 2-acyloxymethyl penams, 3-acyloxy cephams and 3-methyl-.DELTA..sup.3 -cephems by heating a penicillin sulfoxide in the presence of an acid, an acid anhydride, or the like. Generally, when the starting penicillin sulfoxide is reacted in its free acid or salt form the product is decarboxylated, while reaction of the starting penicillin sulfoxide in its esterified form yields a product retaining the esterified carboxyl moiety. The ester group is subsequently removed by, for example, hydrolysis or catalytic hydrogenation.
(B) U.K. Pat. No. 1,409,415 discloses a process for preparing 3-methyl-.DELTA..sup.3 -cephems by heating with an anhydrous acid a penicillin sulfoxide having its carboxyl group protected by a group of the formula ##STR1## in which R.sub.4 and R.sub.5 are the same or different and represent, inter alia, (lower)alkyl, cycloalkyl, phenyl, phenyl(lower)alkyl, (lower)alkoxy, (lower)alkylthio, phenoxy, phenyl(lower)alkoxy, halogen, or a 6-substituted aminopenicillanic sulfoxide-3-carbonyloxy group, or R.sup.4 and R.sup.5 taken together with M.sub.1 represent the residue of a ring system, and M.sub.1 is a boron, aluminum or phosphorus atom; a group of the formula ##STR2## in which R.sub.4, R.sub.5 and R.sub.6 are as described above for R.sub.4 and R.sub.5, or R.sub.4 and R.sub.5 taken together with M.sub.2 represent the residue of a ring system, or R.sub.4 and R.sub.5 together represent oxygen (.dbd.O) or sulfur (.dbd.S), and M.sub.2 is silicon, sulfur, germanium or tin, or a carbon atom when R.sub.4 and R.sub.5 together represent oxygen or sulfur; a group of the general formula ##STR3## in which R.sub.4 and R.sub.5 are as described above and R.sub.7 and R.sub.8 are each halogen or a 6-substituted aminopenicillanic sulfoxide-3-carbonyloxy group, or R.sub.7 and R.sub.8 taken together with M.sub.3 represent the residue of a ring system, or R.sub.7 and R.sub.8 together represent oxygen (.dbd.O) or sulfur (.dbd.S), and M.sub.3 represents phosphorus or tungsten; a group of the general formula ##STR4## in which R.sub.9 is (lower)alkyl, cycloalkyl, phenyl, phenyl(lower)alkyl, (lower)alkoxy, (lower)alkylthio, phenoxy or phenyl(lower)alkoxy, and M.sub.4 represents sulfur; or
(e) the bromo-oxalyl group ##STR5## PA1 R.sup.1 is hydrogen and PA1 R.sup.2 is an amino-blocking group or a conventional acyl group known in the penicillin or cephalosporin art, or PA1 R.sup.1 and R.sup.2, taken together with the nitrogen to which they are attached, may form a phthalimido group, a succinimido group or a group of the formula ##STR16## in which R.sup.9 and R.sup.10 are (lower)alkyl, R.sup.11 is 1,4-cyclohexadienyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic group containing one or more hetero atoms such as sulfur, oxygen and/or nitrogen, e.g. thienyl, furyl, tetrazolyl, thiazolyl or thiadiazolyl; and R.sup.12 is hydrogen, an aldehydo group or a nitroso group; PA1 R.sup.3 is hydrogen, (lower)alkoxy, (lower)alkylthio or ##STR17## in which R.sup.13 is substituted or unsubstituted (lower)alkyl or aryl; --COOR.sup.4 is a protected carboxyl group or a derivative of a carboxyl group; PA1 R.sup.5 is an acyl group, a thioacyl group, a substituted sulfonyl, sulfinyl or sulfenyl group, or a substituted metal or non-metal atom having a valence of from 2 to 5; PA1 n is an integer of from 1 to 4; PA1 R.sup.6 is hydrogen, is the same as R.sup.5, or is ##STR18## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.7 are as defined above, and a and b are the same or different and represent an integer from 0 to n-1, wherein n is as defined above, provided that the sum of a and b is not greater than n-1; PA1 R.sup.7 is hydrogen or the same as R.sup.4 ; and ##STR19## is a conventional acyl group known in the penicillin and cephalosporin art. PA1 (1) acyl isocyanates and thioacyl isocyanates such as acetyl isocyanate, mono-, di- or trichloroacetyl isocyanate, mono-, di- or trifluoroacetyl isocyanate, propionyl and butyryl isocyanates and their chlorinated or fluorinated analogs, phenylacetyl isocyanate, cyanoacetyl isocyanate, benzoyl isocyanate, p-nitrobenzoyl isocyanate, 2,4-dinitrobenzoyl isocyanate, benzyloxycarbonyl isocyanate, p-nitrobenzyloxycarbonyl isocyanate, methoxycarbonyl isocyanate, chloromethoxycarbonyl isocyanate, carbonyl diisocyanate, cyanocarbonyl isocyanate, and the like, as well as their thio analogs, e.g. trichlorothioacetyl isocyanate, chloromethoxythiocarbonyl isocyanate, and the like; PA1 (2) sulfinyl isocyanates of the formula ##STR23## in which Y.sub.4 is as defined above; (3) metal and non-metal tetraisocyanates such as Sn(NCO).sub.4, Se(NCO).sub.4, Ti(NCO).sub.4, Ge(NCO).sub.4, Si(NCO).sub.4, and the like; PA1 (4) substituted metal and non-metal isocyanates of the formula ##STR24## in which M.sub.4 is as defined above and W.sub.4a, X.sub.4a and Y.sub.4a are the same or different and represent substituted or unsubstituted (lower)alkyl, (lower)alkoxy or (lower)alkylthio; or W.sub.4a or both W.sub.4a and X.sub.4a, may be an isocyanate group; or W.sub.4a and X.sub.4a, taken together with M.sub.4, may represent a ring system. Examples of isocyanates falling within this class are (CH.sub.3).sub.3 SnNCO, (CH.sub.3).sub.3 SbNCO, (CH.sub.3).sub.3 GeNCO, (CH.sub.3).sub.3 TiNCO, (CH.sub.3).sub.2 Sn(NCO).sub.2, (CH.sub.3).sub.2 Sb(NCO).sub.2, CH.sub.3 Ti(NCO).sub.3, CH.sub.3 Ge(NCO).sub.3, (C.sub.2 H.sub.5 O).sub.3 SnNCO, (C.sub.2 H.sub.5 O).sub.3 SbNCO, (C.sub.2 H.sub.5 S).sub.3 TiNCO, (C.sub.2 H.sub.5 S).sub.3 GeNCO, (ClC.sub.2 H.sub.4).sub.3 SbNCO, ##STR25## and the like; (5) silyl isocyanates of the formula EQU (W.sub.4).sub.m --Si--(NCO).sub.4-m PA1 in which W.sub.4 is as described above and m is an integer of from 1 to 3. Examples of isocyanates falling within this class include trimethylsilyl isocyanate, dimethylsilyl diisocyanate, methylsilyl triisocyanate, trimethoxysilyl isocyanate, triethoxysilyl isocyanate, triethylsilyl isocyanate, diphenylsilyl diisocyanate, dibenzyloxy diisocyanate, triphenylsilyl isocyanate, tribenzylsilyl isocyanate, (ClC.sub.2 H.sub.4).sub.3 SiNCO, (ClC.sub.2 H.sub.4 O).sub.2 Si(NCO).sub.2, (C.sub.6 H.sub.5 O).sub.2 Si(NCO).sub.2, ##STR26## and the like; and (6) ring compounds of the formula ##STR27## in which M.sub.3a is nitrogen, boron, phosphorus or antimony. ##STR28## in which M.sub.5 is a pentavalent metal or non-metal atom and W.sub.5, X.sub.5, Y.sub.5 and Z.sub.5 are the same or different and represent a substituted or unsubstituted (lower)alkyl, aryl, aryloxy, (lower)alkoxy, or (lower)alkylthio group, or an isocyanate group; or W.sub.5 and X.sub.5, taken together with M.sub.5, represent a ring system; or W.sub.5 and X.sub.5, taken together, represent .dbd.O or .dbd.S. Examples of isocyanates within this class are (C.sub.4 H.sub.9).sub.3 Sb(NCO).sub.2, (CH.sub.3).sub.4 SbNCO, (ClC.sub.2 H.sub.4).sub.3 Sb(NCO).sub.2, ##STR29## in which R.sup.14 is a substituted or unsubstituted (lower)alkyl, aryl, ar(lower)alkyl, cycloalkyl, (lower)alkoxy, aryloxy, ar(lower)alkoxy, (lower)alkylthio, or ar(lower)alkylthio group, or an isocyanate group. Examples of isocyanates falling within this class are methylsulfonyl isocyanate, chloromethylsulfonyl isocyanate, phenylsulfonyl isocyanate, p-nitrophenylsulfonyl isocyanate, 2,4-dinitrophenylsulfonyl isocyanate, toluenesulfonyl isocyanate, phenoxysulfonyl isocyanate, benzyloxysulfonyl isocyanate, ethoxysulfonyl isocyanate, ethylthiosulfonyl isocyanate, sulfonyl diisocyanate, and the like. PA1 (1) Isocyanates of Formula II maintain an anhydrous situation throughout the ring expansion reaction, thus avoiding the water-induced degradation reactions which can occur in catalytic ring expansion processes.
The reaction is run under anhydrous conditions in the presence of silyl compounds which are capable of rapid reaction with the water formed during the ring enlargement reaction and which form either neutral or basic compounds upon hydrolysis. In a preferred embodiment the reaction is conducted in the presence of an excess of a nitrogen containing base. The carboxyl protecting group is subsequently removed by simple hydrolysis.
(C) U.K. Pat. No. 1,421,080 discloses a process for the preparation of compounds of the formula ##STR6## in which either R.sub.1 is a hydrogen atom and R.sub.2 is a phenacetyl, phenoxyacetyl, trityl, optionally protected .alpha.-aminophenacetyl radical (which may contain one or more nuclear substitutents selected from hydroxyl, alkoxy, alkyl-mercapto and halogen radicals), thienylacetyl or tert.-butoxycarbonyl radical; or R.sub.1 and R.sub.2 form, together with the nitrogen atom to which they are attached, a phthalimido or succinimido group; and R.sub.3 is a benzyl, methoxybenzyl, nitrobenzyl, diphenylmethyl, trityl, .beta.,.beta.,.beta.-trichloroethyl, cyanomethyl, 9-fluorenyl, tert.-butyl phenacyl, chlorophenacyl, bromophenacyl, nitrophenacyl, phenylphenacyl, alkoxyphenacyl, or trimethylsilyl radical; in which process a 6-acylaminopenicillanic acid ester of the general formula: ##STR7## (in which R.sub.1, R.sub.2 and R.sub.3 are as defined above) is heated to 60.degree.-150.degree. C. in the presence as a catalyst of a phenol of the general formula: ##STR8## in which R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are identical or different radicals selected from hydrogen, nitro, nitrile and halogen radicals, alkyl and haloalkyl radicals, carbalkoxy radicals, alkylcarbonyl radicals, alkylsulphonyl radicals, benzoyl, phenylsulphonyl and carbophenoxy radicals, and phenyl radicals optionally carrying one or more substituents selected from the radicals given therein as possible meanings for R.sub.4 -R.sub.8 ; provided that in the general formula only one of R.sub.4 -R.sub.8 can be a halogen atom and not more than two of R.sub.4 -R.sub.8 can be hydrogen atoms.
(D) U.S. Pat. No. 4,010,156 discloses a process for preparing 3-halo-3-methylcepham derivatives of the formula ##STR9## in which R.sup.1 is hydrogen or an organic acyl radical; R.sup.2 is hydrogen or, taken together with R.sup.1 -N, may represent phthalimido or ##STR10## in which R.sup.4 and R.sup.5 are hydrogen or (lower)alkyl and R.sup.6 is phenyl or 1,4-cyclohexadienyl; R.sup.3 is hydroxy, (lower)alkoxy, 2,2,2-trichloroethoxy, aryloxy, aralkoxy, alkoxyaralkoxy, mono- or di-(lower)alkyolamino, arylamino saccharimido, phthalimido or OM in which M is an alkali metal cation, an alkaline earth metal cation or the ammonium cation; and A is chloro, bromo or iodo. The compounds are prepared by heating the corresponding penicillin sulfoxide of the formula ##STR11## in which R.sup.1, R.sup.2 and R.sup.3 are as defined above in a polyhaloalkane solvent in the presence of an equimolar amount of any of certain specified quaternary ammonium salt catalysts. The 3-halo compound is then dehydrohalogenated to form the corresponding cephem compound. Alternatively, the cephem compound may be produced in one step from the penicillin sulfoxide by utilizing a basic catalyst such as pyridine instead of the quaternary ammonium salt catalyst.
(E) U.S. Pat. No. 3,997,533 discloses a process for converting penicillin sulfoxide esters to the corresponding 3-methyl-.DELTA..sup.3 -cephem compound by heating in the presence of a heavy metal salt catalyst of the formula EQU Me(R"SO.sub.3).sub.n
wherein Me is copper, silver, gold, zinc, cadmium, mercury, thallium, tin, lead, iron, cobalt or nickel; R" is (lower)alkyl, fluoro(lower)alkyl or substituted or unsubstituted phenyl or naphthyl; and n is 1-3 depending on the valence of Me.
(F) Japanese Patent Publication No. 50-53387 discloses a process for preparing compounds of the formula ##STR12## in which R.sub.1 is hydrogen, acyl or substituted silyl and R.sub.2 is hydrogen, alkyl, aryl, aralkyl or substituted silyl, by heating a penicillin sulfoxide of the formula ##STR13## in which R.sub.1 and R.sub.2 are as described above, in a non-reactive organic solvent, with 1-5 equivalents of an isocyanate of the formula EQU R.sub.3 -(NCO).sub.n
in which R.sub.3 is alkyl, aryl, aralkyl, alkylene or arylene and n is 1-3. It is stated that the reaction is accelerated by the addition of 0.1 mole of pyridine, quinoline or isoquinoline per mole of penicillin sulfoxide. Specifically mentioned isocyanates are phenyl isocyanate, toluene-2,4-diisocyanate, methyl isocyanate, isobutyl isocyanate and hexamethylene diisocyanate. The patent does not teach the use of acyl isocyanates, substituted sulfonyl, sulfinyl or sulfenyl isocyantes, or substituted metal or non-metal isocyanates.
It has been our finding with the above reaction that phenyl isocyanate is not sufficiently reactive to transform a penicillin sulfoxide ester unless a base is present. The transformation of penicillin sulfoxides to cephalosporins is accompanied by the elimination of a mole of water for every mole of 3-methylcephalosporin produced. This water, when scavenged by an alkyl or aryl isocyanate (as in the above patent), gives an alkyl or aryl amine, which in turn may be scavenged by excess isocyanates or by the .beta.-lactam. The latter unwanted reaction may account for poor yields in the above process for ring expansion. Because of this, the reaction of alkyl or aryl isocyanates with penicillin sulfoxides is of no commercial interest. A further drawback of the alkyl and aryl isocyanates is their extreme toxicity. Isocyanates which do not give alkyl or aryl amines, or their derivatives, on hydrolysis were considered by us to offer new prospects not compromised by the production of unwanted side products. Activated isocyanates such as acyl isocyanates, substituted sulfonyl, sulfinyl or sulfenyl isocyanates, and substituted metal and non-metal isocyanates offer a potential which has hitherto been unexamined.
(G) Various excellent reviews of prior art processes for rearrangements and/or ring expansion of penicillin sulfoxides are available. See, for example, R. D. G. Cooper, et al., Accounts of Chemical Research, 6, 32 (1973) and Chapter 5, entitled "Rearrangements of Cephalosporins and Penicillins", in the book Cephalosporins and Penicillins, E. H. Flynn, ed., Academic Press, New York, 1972.
(H) W. German OLS No. 2,704,712 discloses, inter alia the reaction of 3-hydroxymethyl .DELTA..sup.3 -cephems with certain isocyanates to produce the corresponding substituted 3-carbamoyloxymethyl .DELTA..sup.3 -cephems, with optional removal of the substituent group. A specific example was as follows (R.sup.1 =tritylamino): ##STR14##